The evolutionarily conserved Hedgehog (Hh) signaling pathway is essential for embryonic development, tissue homeostasis, and maintenance of self-renewal potential in adult stem cells1-3. An increasing body of evidence has shown that key components of the pathway: Hh protein, its receptor Patched (Ptc) and an effector receptor Smoothened (Smo), also play pivotal roles in the development of numerous cancers3,4. For example, dysregulation of Hh signaling, resulting from mutations in components of the pathway has been directly implicated in the development of basal cell carcinoma and medulloblastoma6-10. High levels of pathway activity are observed in cancers of the pancreas, proximal gastrointestinal tract, and prostates11-13. In mice, about 14-30% of Ptc heterozygous knockout mice develop medulloblastoma and the homozygous deletion of Ptc in GFAP-positive progenitor cells resulted in the development of medulloblastoma in 100% of genetically engineered mice14-15.
Several small molecule inhibitors of the pathway that bind the Smo receptor, such as cyclopamine, IPI-926, and GDC-0449, have been identified with a number of inhibitors under investigation in clinical trials16-21,49. Among these inhibitors, GDC-0449 (Vismodegib) was recently approved by the FDA to treat patients with advanced basal cell carcinoma22-24. Unfortunately, acquired resistance to GDC-0449 was recently described in which an Asp to His point mutation (D473H) was found in the Smo gene. The Smo-D473H mutant receptor is refractory to inhibition by GDC-0449 due to loss of interaction between the drug and receptor17,25. Thus, new Smo inhibitors with pharmacological properties capable of inhibiting wild-type and clinically relevant mutant receptors are needed to overcome acquired drug resistance and extend the duration of response.
A mechanistic understanding of the Hh signaling pathway has evolved over the past decade26. The Hedgehog family of growth factor proteins is comprised of 3 members: Sonic Desert, and Indian Hedgehog, each known to bind the transmembrane receptor Ptc. In the resting, non-ligand bound state, the unoccupied transmembrane receptor Ptc inhibits the activity of the transmembrane protein Smo. Upon binding of Hh ligand to its receptor Ptc, Smo becomes activated and transduces signaling by activating Gli transcription factors that results in the modulation of Hh responsive genes such as Myc and Ptc.
U.S. Pat. No. 8,178,563 to Gao et al. describes compounds and compositions as hedgehog pathway modulators, and therapeutic methods of use thereof.